Table 2.

Mitochondrial disorders with potential to mimic multiple sclerosis

Disorder	Gene(s); molecular genetic pathogenesis	Inheritance mechanism	Clinical presentation in adult-onset disease	‘Typical’ MRI appearances	Recommended diagnostic testing
Leber hereditary optic neuropathy (LHON)	mtDNA: MT-ND4, MT-ND6, MT-ND1; other mtDNA genesa mtDNA mediated degeneration of retinal ganglion cell layer; variable, gender-specific penetrance; effect of environmental modifiers	mitochondrial	Bilateral, painless, subacute visual failure with central field loss in young adult life, typically with more complete penetrance in males; tremor, peripheral neuropathy, myopathy, and movement disorders more common in individuals with LHON than in controls (‘LHON-plus’); females with LHON may develop MS-like illness (‘Harding disease’)	Often normal in patients with ‘pure’ LHON; multifocal WM disease mimicking demyelinating lesions of MS seen in LHON patients with apparently pure optic neuropathy as well as in ‘LHON-plus’ and Harding disease phenotypes	mtDNA sequencing (leucocytes, muscle or cultured fibroblasts) Fundal examination/retinal photography (oedema of peripapillary nerve fiber layer, retinal telangiectasia, increased vascular tortuosity) Visual evoked potentials (absent or delayed) Also consider: Muscle biopsy with respiratory chain activity (partial defects of complex I in some cases) Optical coherence tomography (temporal thickening of RNFL) Electroretinography (exclude retinal dysfunction as cause of visual loss)
MELAS/MERRF	mtDNA: typically MT-TL1 and MT-ND5 in MELAS; MT-TK in MERRF; other mtDNA genesb Decreased activity of respiratory chain complexes or constituent subunits	mitochondrial	Seizures (prominent myoclonus in MERFF), gait instability/ataxia (often initial manifestation in MERFF), myopathy, stroke-like episodes, sensorineural deafness, dementia, PEO, hemianopsia, pigmentary retinopathy, peripheral neuropathy; growth delay, cardiomyopathy, dysrhythmia	MELAS: acute and chronic stroke-like episodes with GM/WM T2/FLAIR hyperintensity, typically involving the posterior cerebrum, thalamus, and not conforming to major vascular territories; in acute phase lesions typically do not restrict diffusion as is seen in ischaemic stroke; elevated lactate on MR spectroscopy; MERRF: multicystic or cavitating leukoencephalopathy, cerebral, cerebellar or brain stem atrophy; basal ganglia calcification/necrosis	Lactate/pyruvate, plasma/CSF (often increased) mtDNA sequencing (muscle or cultured fibroblasts)b,c Muscle biopsy with respiratory chain activity (RRF in MELAS and MERRF; CCO-positive staining in MELAS; partial defects of complexes I and/or IV seen in MELAS; defects of all mtDNA-dependent complexes may be seen in MERRF) Amino acids, plasma (increased alanine) Organic acids, urine (increased lactate metabolites)
Leigh disease	SURF1 and other nuclear genes; MT-ATP6 and other mtDNA genesd Most mtDNA or nuclear mutations cause decreased activity of respiratory chain complexes or constituent subunits; some mutations disrupt tRNAs	AR/X-linked; mitochondrial	Spasticity, dystonia, weakness, hypo- or hyperreflexia, seizures (myoclonic or generalized tonic-clonic; infantile spasms), cerebellar ataxia, peripheral neuropathy; dysphagia, persistent vomiting, thermoregulatory dysfunction; optic atrophy, retinitis pigmentosa; liver and renal disease; cardiomyopathy	Bilateral, symmetrical T2/FLAIR hyperintense lesions in brain stem and/or basal ganglia (especially putamina) are characteristic; lesions affecting the mamillothalamic tracts, substantia nigra, medial lemniscus, medial longitudinal fasciculus, spinothalamic tracts, and cerebellum	Lactate/pyruvate, plasma/CSF (increased) mtDNA (muscle or cultured fibroblastsc) or nuclear gene sequencing Amino acids, plasma (increased alanine)e Also consider: Muscle biopsy and respiratory chain activity (may see intracytoplasmic neutral lipid droplets, RRF rare; CCO-negative fibers seen in individuals with Leigh-related mtDNA mutations; normal respiratory chain activity of isolated defects in complexes I or IV) Nerve conduction studies
POLG-related disease	POLG encodes DNA polymerase gamma required for mtDNA replication and proofreading	ARf	Cerebellar ataxia, sensory ataxia, axonal neuropathy, migraine (often first symptom), encephalopathy, seizures, myoclonus, PEO, myopathy, dysarthria; liver disease	‘MS-like’ T2/FLAIR hyperintense periventricular WM lesions; gadolinium-enhancing brain and cord lesions described	Molecular testing of POLGg Also consider: Muscle biopsy with respiratory chain activity (abnormal respiratory chain enzymology; mtDNA deletion or depletionh) Nerve conduction studies Liver function, plasma
Optic atrophy, type 1	OPA1 Mitochondrial dysfunction or mislocalization in axons; possible haploinsufficiency or gain-of-function mechanism	AD	Some patients with extraocular features early (sensorineural deafness) or in early-mid adulthood (proximal myopathy, cerebellar or sensory ataxia, axonal sensory and/or motor neuropathy); history of insidious, usually asymmetric, decrease in visual acuity usually in childhood or early adulthood	Normal or optic atrophy; some individuals with basal ganglia calcifications, T2/FLAIR-hyperintense periventricular MS-like lesions, non-specific WM lesions, and cortical and cerebellar atrophy	Molecular testing of OPA1 Fundal examination/retinal photography (optic nerve pallor, bilateral and symmetrical; temporal or global) Visual evoked potentials (absent or delayed) Also consider: Electroretinography (exclude retinal dysfunction as cause of visual loss) Optical coherence tomography (thinning of RNFL; normal morphology of photoreceptor layer) Muscle biopsy (features of mitochondrial myopathy)
Pyruvate dehydrogenase (PDH) deficiency	PDHA1 most common; also PDHB, DLAT, PDHX DLD, PDP1; assembly of pyruvate dehydrogenase enzyme complex	X-linked (PDHA1); AR (other forms)	Intermittent or episodic ataxia or other acute neurological symptoms described, especially in male patients; dystonia, seizures, developmental delay, axonal neuropathy	Leigh-like GM appearances; basal ganglia abnormalities; thin corpus callosum, cortical atrophy; MRI may be normal	Lactate/pyruvate, plasma/CSF (elevated, with disproportionate elevation in CSF; blood lactate:pyruvate ratio typically <20:1) Molecular testing of PDHA1 or other genes PDH enzyme complex activity in lymphocytes or fibroblasts (absent or decreased)

AD = autosomal dominant; AR = autosomal recessive; GM = grey matter; MERRF = myoclonic epilepsy with ragged red fibers; MS = multiple sclerosis; PEO = progressive external ophthalmoplegia; RNFL = retinal nerve fibre layer; RRF = ragged red fibres; WM = white matter.

^a Mutations in MT-ND4 (including m.11778G>A, accounting for 70% of all LHON cases), MT-ND6 (including m.14484T>C), MT-ND1 (including m.3460G>A), MT-ND2, MT-ND4L, and MT-ND5 are known to cause LHON.

^b A specific mutation in MT-TL1 (m.3243A>G) is responsible for approximately 80% of all MELAS cases; other mtDNA genes known to harbor mutations in MELAS patients include MT-ND5, MT-TC, MT-TK, MT-TV, MT-TF, MT-TQ, MT-TS1, MT-TS2, MT-TW, MT-CO1, MT-CO2, MT-CO3, MT-CYB, MT-ND1, MT-ND3, and MT-ND6. Four MT-TK mutations (m.8344A>G, m.8356T>C, m.8363G>A, and m.8361G>A) account for >90% of all individuals with a clinical diagnosis of MERRF; m.8344A>G alone accounts for >80% of cases. Rare cases of MERRF are attributable to mutations in MT-TF or MT-TP.

^c Negative selection of leucocytes with high mutant mitochondria burden means that other tissues besides blood (cultured fibroblasts, skeletal muscle) should be used for mtDNA mutational analysis in patients with suspected Leigh disease, MELAS, or MERRF.

^d Other nuclear genes associated with Leigh disease include NDUFV1, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS7, NDUFS8, NDUFA1, NDUFA2, NDUFA10, NDUFAF2, C8orf38, C20orf7, FOXRED1, SDHA, COX10, COX15, LRPPR1, PDSS2, POLG, SUCLG1, and C12orf65. m.8993T>G and m.8993T>C (in MT-ATP6) collectively account for 10–20% of all Leigh disease. Other mtDNA genes implicated in Leigh disease include MT-TL1, MT-TK, MT-TW, MT-TV, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6, and MT-CO3.

^e Decreased citrulline also observed in Leigh disease patients with m.8993T>G mtDNA mutation.

^f All clinical phenotypes of POLG-related disease follow AR inheritance, except PEO, which follows AD inheritance.

^g Oligonucleotide array should be strongly considered if there is reasonable clinical suspicion for POLG-related disease, as microdeletions involving intragenic regions of POLG are reported and therefore relevant in a symptomatic individual with a single heterozygote pathogenic mutation.

ⁱ Normal analysis of skeletal muscle for mtDNA depletion/multiple deletions and respiratory chain enzymology does not exclude POLG-related disease.